Obesity is a worldwide health epidemic and a major contributor to the increased prevalence and severity of more than 60 metabolic, inflammatory, degenerative, cognitive, and neoplastic disorders. Broadly effective preventive and therapeutic strategies have been elusive, and rates of obesity continue to increase worldwide. Among the current therapies for obesity, bariatric or gastrointestinal weight loss surgery (GIWLS) generally, and Roux-en-Y gastric bypass (RYGB) in particular, has proven to be the most effective and durable by far. Recent studies have revealed, unexpectedly, that RYGB works primarily by altering the physiological control of energy balance and body fat storage. It affects a wide variety of physiological systems, including the regulation of ingestive behavior, energy expenditure and glucose homeostasis. In contrast to restrictive diets, surgery-induced weight loss is associated with decreased hunger and hedonic drive to eat, increased satiety, and in rodent models at least, increased diet-induced thermogenesis. Moreover, the beneficial effects of this operation on diabetes and other metabolic disorders appear to include mechanisms independent of weight loss or diminished food intake. These characteristics suggest that defining the mechanisms of action of RYGB will provide a valuable roadmap for the development of new and more effective therapies and may uncover novel biomarkers of response to treatment or preventative strategies. The widespread effects of RYGB suggest that GIWLS is a powerful new tool for exploring the physiological regulation of metabolic function more broadly. Although rodent models provide an attractive means of studying the therapeutic mechanisms of RYGB, the physiological regulation of energy balance, ingestive behavior and glucose homeostasis in rodents diverges from humans in ways that may limit the applicability of rodent models to human disease. Some of these limitations can be overcome by studying humans directly;however, many experiments require interventions or assessments that are too invasive for human experimentation. For such studies, examination of nonhuman primates (NHPs) provides an attractive alternative. The combination of biological relevance and experimental flexibility provided by NHPs is particularly attractive for the study of central nervous system (CNS) and pancreatic contributors to the response to RYGB, since isolation, pathological examination and manipulation of these tissues in humans is difficult. We propose to examine the physiological effects of RYGB in the Rhesus macaque, a species of NHP that, like many humans, is susceptible to the weight gain and diabetes-promoting effects of a high fat diet. The aims of the project are (1) to establish a model of RYGB in obese Rhesus macaques and to characterize its effects on food intake, ingestive behavior, food preference and energy expenditure, phenotypes that appear highly responsive to RYGB in humans and rodents;(2) to characterize the effects of RYGB on glucose homeostasis and determine the mechanisms of these effects and the degree to which they are dependent on changes in food intake or body weight;(3) to characterize the effect of RYGB on the hypothalamic circuitry regulating ingestive behavior and energy balance;and (4) to examine the broad metabolic response to RYGB through gene expression and metabolic profiling of peripheral and portal venous blood, selected brain nuclei, pancreatic islets, liver and muscle. The proposed studies will increase our understanding of the mechanisms by which the GI tract, pancreas and CNS regulate metabolic function. They will also help to identify the mechanisms underlying the therapeutic benefits of RYGB itself, thereby contributing to the identification of new, more effective therapies for obesity and its myriad complications. PUBLIC HEALTH RELEVANCE: This project aims to exploit the unique characteristics and advantages of the nonhuman primate (NHP) model to explore the mechanisms by which Roux-en-Y gastric bypass (RYGB) alters (1) central control of energy balance and glucose homeostasis, (2) pancreatic endocrine physiology and (3) portal and systemic metabolite flux. It focuses on specific areas of physiological response, including nutrient sensing within the hypothalamus and dynamic regulation of pancreatic islet cell growth and function that are less well conserved between rodents and humans and for which well-characterized rodent models of RYGB are inadequate. The proposed studies require long-term invasive monitoring and tissue collection that is not possible in human subjects, but which can be achieved in the NHP model. The results of these studies will provide important new information about the mechanisms by which RYGB induces durable weight loss and remission of type 2 diabetes in primates, thus facilitating the development of novel approaches that mimic these effects less invasively in human patients.